Pharmacokinetics of ftorafur-2-14C in rats with Walker's carcinosarcoma

The pharmacokinetics of ftorafur-2-¹⁴C (FF) after intravenous injection was investigated in experiments on rats with Walker's carcinosarcoma. The level of FF and its metabolites in the blood plasma was shown to fall in the manner of a three-phase process. The concentration of the compound in the tissues falls in the order: kidneys, small intestine, tumor, stomach, muscles, heart, liver, lungs, spleen, brain, and fat. The presence of FF-2-¹⁴C and its metabolite, endogenous 5-fluorouracil, was observed in the tumor. Excretion of the compound continued for 48 h, 52.2% being excreted through the kidneys, 38% through the lungs, and 0.8% of the injected dose with the feces.Laboratory of Biochemistry and Pharmacokinetics, Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov). Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 6, pp. 734–736, June, 1977.     

Surface coat variant antigen of Trypanosoma brucei brucei: its clearance from blood and concentration in organs of normal, infected, and immune mice.

Experiments were conducted to determine the fate of variant antigen once it was shed from the surface of Trypanosoma brucei brucei. Radioiodinated variant antigen was administered intravenously to normal mice, mice immunized to the homologous variant antigen, and mice infected with an antigenically dissimilar (heterologous) T. brucei brucei variant. The variant antigen was cleared slightly faster in infected and immune animals. Though over 80% of the variant antigen was cleared in all animals within 4 h, traces of radioactivity could be detected in the peripheral blood at 48 h postinjection. At 1 h postinjection, most of the variant antigen had collected in the liver, kidneys, bone marrow, spleen, lungs, thymus, and lymph nodes (listed in the order of decreasing radioactivity). At 24 h, the kidneys, liver, and spleen retained the most radioactivity. The kidneys had 10 to 20 times, the liver had 8 to 10 times, and the spleen had 5 to 7 times more variant antigen than was present in the organs' blood supply. At 48 h postinjection, two-thirds of the radioactivity present at 24 h remained in these tissues. The livers and spleens from infected animals had, on a per gram of tissue weight basis, reduced uptake of the soluble antigen whereas their lungs had an increased uptake. Radioactivity in blood and organs was proved to be associated with protein by electrophoresis/autoradiography and precipitation of radioactive protein of tissue extracts.     

Interferon Induction by Poly(I):Poly(C) Enclosed in Phospholipid Particles

Liposomes were prepared with phospholipids (sphingomyelin, lecithin, and phosphatidylethanolamine) in combination with cholesterol and charged lipids (dicetyl phosphate and stearylamine) and contained either poly(I):poly(C) or poly(I). Neutral and positively charged liposomes attached much better to L-929 cells in tissue culture than did negatively charged particles. Liposomes were toxic to L cells at relatively low concentrations, making the determination of antiviral activity induced by particles containing poly(I):poly(C) difficult to measure by the plaque reduction assay. When injected into mice, all of the liposomes containing poly(I):poly(C), except phosphatidylethanolamine liposomes, greatly potentiated and extended the serum interferon response of poly(I):poly(C). Lecithin and sphingomyelin liposomes given intravenously were ten times more effective than free poly(I):poly(C) in stimulating production of serum interferon. Sphingomyelin liposomes containing [(14)C]poly(I):poly(C) were 88% cleared from the bloodstream of mice by 3 min after intravenous injection. Most of the radioactivity (70%) was captured by the liver and remained there for at least 4 h. By 2 h, 7% of the radioactivity could be found in the spleen. Five percent of the radioactivity was found in the lungs at 30 min, with decreasing amounts thereafter. Small amounts of radioactivity were found in the muscle and kidneys. The spleen was shown to contain appreciable levels of interferon at 4 h, and low levels were found in the liver. Radioactivity accumulated slowly in the liver following an intraperitoneal injection of sphingomyelin liposomes containing [(14)C]poly(I):poly(C). By 4 h, 26% of the dose was recovered from the liver and 4.9% from the spleen, with small amounts in the lung, kidney, and omentum.     

Selective accumulation of monoclonal antibodies against neurospecific enolase in brain tissue of rats with middle cerebral artery occlusion

Preparations of I¹²⁵-labeled monoclonal antibodies against neurospecific enolase and mouse plasma IgG1 were injected intravenously to rats immediately after unilateral occlusion of the middle cerebral artery. Radioactivity of I¹²⁵-labeled monoclonal antibodies against neurospecific enolase in the brain tissue progressively increased, reached a maximum by the 48th hour, and remained practically unchanged after 72 h. At the same time radioactivity of labeled IgG1 in the brain tissue and radioactivity of both preparations in the blood, liver, spleen, kidneys, heart, and lungs decreased over 72 h. Selective accumulation of I¹²⁵-labeled monoclonal antibodies against neurospecific enolase was less significant in the brain tissue of the contralateral hemisphere and cerebellum not exposed to ischemia.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 10, pp. 388–392, October, 2004     

Selective accumulation of monoclonal antibodies against neurospecific enolase in brain tissue of rats with middle cerebral artery occlusion

Preparations of I¹²⁵-labeled monoclonal antibodies against neurospecific enolase and mouse plasma IgG1 were injected intravenously to rats immediately after unilateral occlusion of the middle cerebral artery. Radioactivity of I¹²⁵-labeled monoclonal antibodies against neurospecific enolase in the brain tissue progressively increased, reached a maximum by the 48th hour, and remained practically unchanged after 72 h. At the same time radioactivity of labeled IgG1 in the brain tissue and radioactivity of both preparations in the blood, liver, spleen, kidneys, heart, and lungs decreased over 72 h. Selective accumulation of I¹²⁵-labeled monoclonal antibodies against neurospecific enolase was less significant in the brain tissue of the contralateral hemisphere and cerebellum not exposed to ischemia.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 10, pp. 388–392, October, 2004     

The fate of radioiodinated sheep-growth hormone in intact and nephrectomized sheep

Summary The metabolic clearance rate of¹²⁵I-labelled sheep growth hormone (GH) in intact sheep was calculated to be 61±7.8 l/24 h and in nephrectomized sheep 26±3.9 l/24 h. From these figures a production rate of GH of 122 g/24 h was derived for intact sheep.After a single intravenous injection of labelled GH the kidneys extracted more than 90% within 4 h. The extracted GH was metabolized by the kidney, only a small amount (5%) of the radioactivity excreted in the urine could be precipitated by perchloric acid. Renal metabolism of GH was also indicated by the appearance in renal venous blood of labelled material that was not immunoprecipitable. The liver also removed labelled GH and degraded it.Four hours after the injection of labelled GH most of the radioactivity was in blood and muscle, but there were significant amounts in kidney, liver and fat. Radioactivity that could be precipitated with GH-antiserum was found only in the kidney, thyroid and blood. A high percentage of activity extracted from all these tissues could still be precipitated by perchloric acid.     

Biocompatibility and Resorption of Intravenously Administered Polymer Microparticles in Tissues of Internal Organs of Laboratory Animals

Specimens of ¹⁴C-labeled polymer of 3-hydroxybutyric acid, P(3-HB), with different initial molecular weights, were used to prepare microparticles, whose morphology was not influenced by the M _w of the polymer. During the particle preparation process, P(3-HB) molecular weight decreased by 15–20%. Sterile microparticles (mean diameter 2.4 μm) were injected into the tail veins of Wistar rats (5 mg/rat). The effects of the particles administered to rats were studied based on the general response of animals and local response of internal organ tissues and blood morphology; no adverse effects on growth and development of the animals or unfavorable changes in the structure of the tissues of internal organs were observed. Measurements of radioactivity in tissues showed that ¹⁴C concentrations are different in different organs, changing during the course of the experiment. The main targets for ¹⁴C-labeled microparticles were tissues of the liver, spleen, and kidneys. Comparison of radioactivity levels and residual contents of high-molecular-weight matrix in tissues suggested that the most rapid metabolism and degradation of P(3-HB) occurred in the liver and spleen. Gel-permeation chromatography showed that at 3 h after the microparticles were injected into the bloodstream, polymer degradation started in all examined organs, except the lungs; at 12 weeks, the M _w of the polymer matrix was as low as 20–30% of its initial value. The presence of high-molecular-weight (undegraded) polymer in the tissues at 12 weeks after administration of the particles suggests that P(3-HB) is degraded in tissues of internal organs slowly and, hence, P(3-HB)-based microparticles can be used as sustained-release drug-delivery systems.     

Pulmonary, hepatic and splenic sequestration of technetium-99m labelled autologous rabbit granulocytes: scintigraphic cell distributions after intravenous and intraarterial injections, exsanguination and intraarterial injection of cells passed through an intermediary host

In man, about half the intravascular granulocytes are not freely circulating, but temporarily sequestered ('marginated'), so that they cannot be retrieved by bleeding. Where and how the sequestration occurs is not settled and is the subject of the present report. Isolated autologous rabbit granulocytes, labelled with two different 99mTc methods, were reinjected and followed with external scintigraphy. Intraarterial as well as intravenous injection led to rapid accumulation of radioactivity over the lungs. This finding was corroborated and extended by similar experiments, where the labelled cells had firstly been passed through an intermediary rabbit host to remove altered cells, i.e. cells damaged, 'primed' (pre-activated), or activated. In the final autologous host about two thirds of the label rapidly localized to the lungs and liver, and a few per cent to the spleen (which is very small in the rabbit). Even though more than half of the intermediary rabbit's calculated blood volume was removed, the blood sample contained only a few per cent of the rabbit's radioactivity; consequently, many of the labelled leucocytes had marginated during the bleeding. The proportional distribution of radioactivity over lungs, spleen, kidneys, and the rest of the intermediary animal was not markedly changed by this exsanguination, but there was a 4-20% decrease over the liver. Taken together, our findings indicate that normal granulocytes marginate in lungs, liver, and spleen--apparently explicable by the effects of cell size, vessel diameter, cell stiffness (visco-elastic properties) and size of the arterio-venous hydrostatic pressure difference. The liver and spleen seemed to play additional roles, since radioactivity over these organs decreased much slower than expected from reported blood half-times of intact and slightly damaged rabbit granulocytes. This led to a suggestion that macrophages exposed to blood normally phagocytose apoptotically dying granulocytes.     

The Fate of Intravenously Administered Radioactive Cholesterol Dispersion in the Rat

The present work was aimed at studying the first stages of disappearance of particulate cholesterol from the circulation. The distribution of radioactivity in blood, liver, spleen, lungs and kidneys was determined at different time intervals after i.v. injections of aqueous-ethanolic dispersions of radioactive cholesterol to rats. More than 95% of the dose disappeared from the circulation in 10 min. From 71 to 93% of the dose was found in the liver 5 min-2 h after the injection. According to autoradiography, most of the particulate cholesterol was immediately taken up by the liver parenchymal cells. There were only few grains over the Kupffer cells. 2 min to 6 h after the injection the highest specific radioactivity was in the free cholesterol fraction of the liver. The specific activity of liver esterified cholesterol was 54 % of that of the free cholesterol at 1 h. They both declined gradually and reached the same level in 1–2 days. There was a gradual rise of the specific activities of plasma free and esterified cholesterol starting 30 min after the injection. Both reached a maximum in 6–16 h, when the curve of plasma esterified cholesterol intersected that of liver esterified cholesterol. The radioactivity reappearing in plasma was associated with lipoproteins and red cells; the cholesterol of the high density lipoproteins had the highest specific activity. The results indicate that particulate cholesterol is taken up chiefly by the parenchymal cells of the liver and is subsequently incorporated into the plasma lipoproteins, most rapidly into the high density lipoproteins. A large fraction of plasma esterified cholesterol originates in the liver.     

Intravasation of Fat from the Bone Marrow Cavity

Fat labeled with triolein-¹³¹I was introduced through a burr hole into single tibial marrow cavities and the hole was sealed. The radioactivity over the thorax was monitored for 2-5 hours. After sacrifice, the radioactivity was determined in lungs, injected tibia or leg, kidneys, brain, thyroid gland and blood. Presence of pulmonary embolic fat was verified by histologic methods. Intravasation occurred after closure of the burr hole; it was delayed in several animals and failed to occur in 1 animal. The following mean percentages of the injected activity were found: in lungs 44.8% (0.04-85.1%); in tibia 44.7% (7.1-96.8%); in other investigated tissues and organs collectively, less than 1%. In another group, the tibia was fractured either immediately after injection of the labeled fat and closure of the burr hole, or while intravasation was in progress. After 2-5 hours, the lungs contained 23.2% (0.1-65.6) of the labeled fat, which was significantly less than in animals without fracture. In 2 animals, the needle was sealed into the burr hole, and the pressure necessary to produce intravasation was measued. A pressure of 50-100 mm of H₂O produced pulmonary fat embolism as rapidly as the fat was injected.     

Distribution of prolactin in selected rat organs and tissues

A single dose of 25 microg prolactin (PRL)/kg of rat body weight was administered to rats subcutaneously. At 1, 2, 3, 4 and 5 h after the injection, selected organs and tissues were taken for analysis. It was found that 1 h after administration, the highest amount of PRL accumulated in the milk (lactiferous) gland, the blood, the ovaries, the pituitary and the liver. Over time, the prolactin content in the selected organs and tissues decreased. PRL is selectively captured by the milk gland, the pituitary, the ovaries, the liver and the heart. Based on the value of the organ or tissue capacity index for PRL, the following order was established for the organs and tissues to which the hormone binds: milk gland > blood > pituitary > ovaries > lungs > liver > cranial bone > spleen > heart > kidneys > muscular tissue > adrenals > adipose tissue > brain.     

Distribution of 3H-labeled staphylococcal alpha-toxin and a toxin fragment in mice.

Staphylococcal alpha-toxin and a toxin fragment were labeled with N-succinimidyl[2,3-3H]propionate. The labeled compounds retained greater than 95% biological activity. The distribution of labeled staphylococcal alpha-toxin and alpha-toxin fragment after intravenous administration to BALB/c mice was studied with whole-body and microautoradiography. The animals were divided into three groups that received (i) labeled alpha-toxin only, labeled alpha-toxin after prior injection of unlabeled fragment, or labeled fragment only. After 5 min, the distribution patterns were similar in groups 1 and 2, with the highest amounts of radioactivity found in the blood vessels, liver, spleen, lungs, and kidneys, whereas the labeled fragment alone showed no initial accumulation in the lungs. The kidneys continued to show a high concentration of radioactivity, whereas the levels at 60 min had decreased in the other organs. The toxin showed continued stable binding to the proximal tubuli, whereas the toxin fragment seemed to dissociate and was found only in small amounts in the glomeruli. No radioactivity was found in the central nervous system.     

Histopathologic and ultrastructural studies of disseminated cytomegalovirus infection in strain 2 guinea pigs

Inbred strain 2 guinea pigs developed severe disseminated disease during acute experimental guinea pig cytomegalovirus (GPCMV) infection. A high mortality rate (100%) resulted, with most animals dying between 10 and 14 days after high dose (7.5 X 10(5) TCID50) virus inoculation. Infectious virus was recovered from many tissues, including spleen, lungs, liver, pancreas, heart, adrenals, kidneys, and salivary glands. The rate of GPCMV isolation from these tissues ranged from 50 to 100%. Gross lesions were observed in the spleen, liver, and lungs. On histologic examination, lesions were also seen in many other organs, including heart, pancreas, kidneys, adrenals, brain, intestines, and salivary glands. Intranuclear viral inclusions were present in many cell types of various organs. Under electron microscopic examination, cells with viral inclusions were easily found in the spleen, and liver, but less readily in the lungs, kidneys, salivary glands, and other organs. Most of the intranuclear inclusions consisted of electron-dense fibrils (10 nm diameter), viral nucleocapsids (100 nm), and tubular structures (60 nm diameter). Dense bodies and enveloped dense virions containing single or multiple capsids were present in the cytoplasm of many infected cells. The morphologic developments of GPCMV in these visceral tissues of strain 2 guinea pigs resembled those seen in GPCMV-infected cultured guinea pig cells but differed from those observed in the infected salivary gland duct cells. Strain 2 guinea pigs are a useful animal model for studying disseminated infection in CMV-associated human diseases.     

Uptake and Killing of Mima polymorpha and Herellea vaginicola by the Reticuloendothelial System of Neonatally Thymectomized Nonwasted Mice

Phagocytosis and killing of Mima polymorpha and Herellea vaginicola by the liver, lungs, spleen, and kidneys from neonatally thymectomized nonwasted mice and their sham-thymectomized litter mates were compared. The removal of M. polymorpha from blood by these organs, measured 2 and 4 hr after intravenous injection of bacteria, was not affected by thymectomy. Because significantly fewer viable organisms persisted in the liver, spleen, and kidneys, it is concluded that bacterial killing increased after thymectomy. Phagocytosis of M. polymorpha by peritoneal macrophages increased in thymectomized mice. Removal of H. vaginicola from the blood by the lungs was greater after thymectomy. Thymectomy did not affect the killing of H. vaginicola by the liver, spleen, lungs, or kidneys. Killing of H. vaginicola by the kidney was less than that by other organs, although this was not affected by thymectomy. Chronic reticuloendothelial stimulation associated with infection was not an adequate explanation for these findings because no wasting syndrome was encountered.     

The effect of ribonucleic acid and its hydrolyzates on the uptake of glycine-1-C14 by proteins of normal and tumor tissues

Summary Ribonucleic acid and its hydrolyzates exert a stimulating effect on the incorporation of glycine-1-C¹⁴ into the proteins of minced normal organs (pancreas, liver, kidneys, spleen, brain, and thymus) of rats and have almost no effect on the incorporation of glycine radioactivity into the proteins of minced sarcoma M-1 and transplanted cholangioma at late stages of its growth. At early stages of cholangioma growth some stimulation of radioactivity incorporation is noted. The effect of the stimulation is independent of the length of RNA hydrolysis.Presented by Active Member AMN SSSR A. E. Braunshtein     

Localization of 125I-labelled α-r-atrial natriuretic peptide in rat tissues by whole-body and microautoradiography

¹²⁵I-labelled α rat atrial natriuretic peptide (28 amino acids: Ser 99–Tyr 126) ([¹²⁵I]α-rANP) was given i.v. to Sprague—Dawley rats and the distribution of radioactivity in the tissues was examined by whole-body and microautoradiography at intervals from 2 min to 4 h after the administration. Inhibition of uptake of the [¹²⁵I]α-rANP by simultaneous injection of an excess of non-labelled α-rANP was taken as an indication that highly labelled structures in rats injected with [¹²⁵I]α-rANP alone are due to an abundance of specific receptors for the peptide. In the rats given only the [¹²⁵I]α-rANP a rapid and high radioactivity occurred in the renal glomeruli, the endocardium of the heart ventricles, the endothelium of the processus ciliares of the eyes, the portal vessels and a few larger vessels of the liver, the subcapsular vessels of the adrenal glands and the parenchyma of the lungs. Other tissues showing a distinct, but less prominent, radioactivity were the endocardium of the heart atria, the walls of the great afferent and efferent vessels in the thoracic cavity, the choroid plexuses of the brain ventricles, the pia mater, brown fat, the muscularis layer of the stomach and the intestines, the lamina propria of the villi in the small intestine and the walls of a few small blood vessels in the kidney medulla. The specific labelling was highest at 2 min after injection and then diminished at later intervals. Several of the labelled structures are localized in tissues involved in the regulation of blood pressure, and fluid and electrolyte homeostasis, processes in which the atrial peptides are considered to play a role. It is suggested that high concentrations of receptors are present at the sites at which the [¹²⁵I]α-rANP was strongly localized and that biological effects of the atrial peptides are exerted via these structures.     

LocaIization of 125l-labelled α-r-atriaI natriuretic peptide in rat tissues by whole-body and microautoradiography

¹²⁵I-labelled α rat atrial natriuretic peptide (28 amino acids: Ser 99-Tyr 126) ([¹²⁵I] α-rANP) was given i.v. to SpragueDawley rats and the distribution of radioactivity in the tissues was examined by whole-body and microautoradiography at intervals from 2 min to 4 h after the administration. Inhibition of uptake of the [¹²⁵1]α-rANP by simultaneous injection of an excess of non-labelled α-rANP was taken as an indication that highly labelled structures in rats injected with [¹²⁵I]α(-rANP alone are due to an abundance of specific receptors for the peptide. In the rats given only the [¹²⁵I]α-rANP a rapid and high radioactivity occurred in the renal glomeruli, the endocardium of the heart ventricles, the endothelium of the processus ciliares of the eyes, the portal vessels and a few larger vessels of the liver, the subcapsular vessels of the adrenal glands and the parenchyma of the lungs. Other tissues showing a distinct, but less prominent, radioactivity were the endocardium of the heart atria, the walls of the great afferent and efferent vessels in the thoracic cavity, the choroid plexuses of the brain ventricles, the pia mater, brown fat, the muscularis layer of the stomach and the intestines, the lamina propria of the villi in the small intestine and the walls of a few small blood vessels in the kidney medulla. The specific labelling was highest at 2 min after injectian and then diminished at later intervals. Several of the labelled structures are localized in tissues involved in the regulation of blood pressure, and fluid and electrolyte homeostasis, processes in which the atrial peptides are considered to play a role. It is suggested that high concentrations of receptors are present at the sites at which the [¹²⁵I]α-rANP was strongly localized and that biological effects of the atrial peptides are everted via these structres.     

Blood protein coating of gold nanoparticles as potential tool for organ targeting

Nanoparticles (NP) and nanoparticulated drug delivery promise to be the breakthrough for therapy in medicine but raise concerns in terms of nanotoxicity. We present quantitative murine biokinetics assays using polyelectrolyte-multilayer-coated gold NP (AuNP, core diameter 15 and 80 nm; ¹⁹⁸Au radio-labeled). Those were stably conjugated either with human serum albumin (alb-AuNP) or apolipoprotein E (apoE-AuNP), prior to intravenous injection. We compare the biokinetics of protein-AuNP-conjugates with citrate-stabilized AuNP (cit-AuNP). Biokinetics was complemented with histology in organs with high AuNP content using 15 nm double fluorescently-labeled alb-AuNP-conjugates. Protein conjugation massively reduced liver retention (alb-AuNP: 52%, apoE-AuNP: 72%, cit-AuNP: >95%, at 19 h and 48 h) when compared to cit-AuNP. The protein conjugates were retained in lungs (alb-AuNP (18%) and spleen (alb-AuNP (16%), apoE-AuNP (21%) at 19 h. Alb-AuNP show significantly increased fractions in lungs (factors: 60 (30 min); 111 (19 h); 235 (48 h) and brain (factors: 70 (30 min); 90 (19 h); >200 (48 h) compared to cit-AuNP (control) - or even to apoE-AuNP. The influence of protein conjugation on the biodistribution disappears for 80 nm AuNP comparing to control. Histologically, the 15 nm alb-AuNP are mainly located in the endothelium of brain, lungs, liver and kidneys after 30 min, while at 19 h they moved deeper into the parenchyma e.g. in hippocampus. Our study clearly suggests that stable conjugation of AuNP with albumin and apoE prior to intravenous administration increases specificity and efficiency of NP in diseased target-organs thus suggesting a potential role in nanomedicine and nanopharmacology.     

Distribution and binding of radioactivity in the starling after intravenous administration of [14C]3-chloro-p-toluidine.

Ring labeled avicide [¹⁴C]3-chloro-p-toluidine HCl (CPT) was injected (14.7 μCi) by intravenous route to starlings. The radioactivity was found to be unevenly distributed in different parts of the body. The retention half-life of radioactivity in brain, spleen, heart, and bone marrow was approximately similar to that of the plasma and ranged from 3–6 hr. A longer retention of radioactivity (8–14.6 hr) than that of the plasma was found in the muscle, lung, liver, and kidney. Of the nine tissues examined, a substantial amount of [¹⁴C]CPT radioactivity was found covalently bound only to liver and kidney proteins. The extent of covalent binding to kidney protein always exceeded the binding to liver protein. Microscopic examination of liver and kidney sections prepared from the birds 12 hr after [¹⁴C]CPT injection revealed marked histopathological changes in the liver and somewhat less striking changes in the kidney. The changes in liver were vacuolation and varying degrees of necrosis ranging from focal to diffuse. In kidney, the pathological changes included hyaline granularity of the cytoplasm. Pretreatment of birds with a microsomal enzyme inducer, phenobarbital, or tissue glutathione depletor, diethylmaleate, had no effect on covalent binding of [¹⁴C]CPT radioactivity to liver protein. These pretreatments, however, enhanced the binding significantly to kidney protein without producing any significant effect on kidney pathology. SKF 525A in phenobarbital pretreated birds had a marked inhibitory effect on covalent binding of [¹⁴C]CPT radioactivity to liver protein. Various explanations have been offered to account for the discrepancy regarding the lack of a positive correlation between the extent of covalent binding of [¹⁴C]CPT radioactivity and tissue lesion in starlings. It has been postulated that an hydroxylamine metabolite of the parent compound possibly binds to liver protein and is responsible for hepatic necrosis.     

Pharmacokinetics of amphotericin B in serum and tissues in mice treated with amphotericin B-Intralipid.

In our previous research we studied the efficacy of amphotericin B (AMB)-Intralipid (AMB-IL) admixtures in the treatment of experimental systemic candidosis in na?ve and compromised mice. In this study we evaluated the levels of AMB in blood and several organs (kidneys, liver, spleen, lungs and heart) at different times after injection (from 5 min to 14 days). Comparisons were made with levels occurring in animals treated with Fungizone or AmBisome. A sensitive high-pressure liquid chromatography (HPLC) method was adapted for assaying AMB in blood and tissues. We used reversed-phased column and a simple mobile phase consisting of acetonitrile and EDTA. We found that blood levels of AMB in mice injected with AMB-IL were higher than those obtained in animals treated with Fungizone, but similar to those obtained in mice administered AmBisome. Compared with conventional Fungizone therapy, administration of lipid formulations of AMB (both AMB-IL and AmBisome) resulted in higher concentrations of AMB in the liver and spleen, but lower concentrations in the kidneys and lungs.